Diabetes is a leading cause of death and disability in the United States. Diabetes requires a lifetime medical treatment. Some diabetes drugs could be taken orally, while others require daily injection or inhalation to maximize bioavailability and minimize toxicity. Parenteral delivery is a group of delivery routes which bypass human gastrointestinal track. Among all the parenteral methods, we chose subcutaneous implant based on its fast act and high patient compliance. When using subcutaneous implant, drug release needs to be strictly controlled. There are three major groups of controlled release methods. Solvent controlled system is already used as osmotic implant. Matrix controlled system is used in Zoladex® implant to treat cancer. Membrane controlled systems is widely used in coating tablets, but not that popular as an implant. Based on the research reported by previous scientists, we decided to build a hybrid system using both matrix and membrane control to delivery human insulin and other small molecule drugs. Subcutaneous environment is different from human GI track. It has less tolerance for external materials so many polymers cannot be used. From the FDA safe excipient database, we selected albumin as our primary polymer and gelatin as secondary choice. In our preliminary insulin diffusion study, we successfully found that insulin mixed with albumin provided a slower diffusion rate compared with control. In addition, we added zinc chloride, a metal salt that can precipitate albumin. The insulin diffusion rate is further reduced. The preliminary study proved that matrix control using albumin is definitely feasible and we might add zinc chloride as another factor. In order to fabricate an implant with appropriate size, we use lyophilisation technology to produce uniformly mixed matrix. Apart from albumin and human insulin, we added sucrose as protectant and plasticizer. The fine powder after freeze-dry was pressed as a form of tablet. The tablets were sealed in Falcon® cell culture insert. Cell culture insert provide a cylinder shape and 0.3 cm2 surface area for drug release. Insulin release study provided a zero order kinetics from prototypes with zinc chloride or 0.4 micron pore size membrane. Caffeine was used as a model drug to investigate the releasing mechanism. Three pore size membranes (0.4, 3 and 8 micron) were tested with same formulation. While 0.4 micron prototypes provided the slowest release, 3 micron ones surprisingly released caffeine faster than 8 micron implants. We calculated the porosity with pore size and concluded that the percentage of open area on a membrane is the key point to control caffeine release. 0.4 micron membranes were used for future research. We increased the percentage of albumin in our excipient, and achieved a slower caffeine release. However, the zero order release could only last for 3 days. After we replaced sucrose with gelatin, a 5 day zero order release of caffeine was achieved. With all the results, we proposed our “Three Phase” drug release mechanism controlled by both membrane and matrix. Seven other small molecule drugs were tested using our prototype. Cloudy suspension was observed with slightly soluble drugs. We updated our “Three Phase” drug release mechanism with the influence of drug solubility. Data shows that releasing rate with same formulation and membrane follows the solubility in pH 7.4. This result proves that our prototype might be used for different drugs based on their solubility. Finally, with all the information of our prototype, we decided to build a “smart insulin implant” with dose adjustment. We proposed an electrical controlled implant with different porosity membranes. Solenoid was used as the mechanical arm to control membrane porosity. 3-D printing technology was used to produce the first real prototype of our implant. Finally, insulin implant with clinically effective insulin release rate was achieved. / Pharmaceutical Sciences

There has been a significant increase in the number of injectable pharmaceutical products over the last decade that have been incorporated into unique delivery systems such as pen injectors, auto-injectors, or pre-filled syringes. The advancement of these delivery systems and the paradigm shift towards administration of injectables in the out-of-hospital or home setting have introduced variables that can affect the bioavailability of injectable drugs and potential pharmacologic outcomes. An approach that allows for the qualitative and quantitative dispersion assessment of an injectable at the moment of tissue deposition coupled with an assessment of systemic exposure parameters could provide substantial information to researchers developing new injectable formulations and associated delivery systems. The overall goal of this research project was to develop an approach for investigating various injection dynamics, more specifically, dispersion dynamics associated with the administration of parenteral pharmaceutical products utilizing delivery technologies designed to deliver drug below the dermis. This was accomplished by first evaluating the safety and usability of computed tomography (CT) scanning as a novel radioimaging approach to assess qualitative and quantitative dispersion parameters in a cadaver study followed by a randomized, controlled, clinical study to assess CT tissue dispersion and the systemic exposure of iohexol, administered subcutaneously by two delivery systems in human volunteers. The primary finding of this work was the demonstration that CT scanning may be combined with a systemic exposure assessment to provide an effective paradigm for investigating dynamics of injectable delivery impacted by a variety of factors, including the choice of delivery system. In this study, iohexol delivered subcutaneously by an auto-injector resulted in notable qualitative and quantitative dispersion differences, including a higher rate of iohexol loss from the extravascular tissue, as well as differences in early plasma exposure as compared to a pre-filled syringe delivery system. The injections and CT scanning were well tolerated with adverse events limited to mild injection site reactions resolving without intervention. This research resulted in a novel local in-vivo(extravascular disappearance), systemic in-vivo(intravascular appearance) correlation approach that could be utilized to assess a wide variety of dynamics associated with injectable drug delivery below the dermis.